The invention relates to a method of using tetracycline compounds in the treatment of diabetes. Specifically, the invention relates to a therapeutic method of using tetracyclines in managing patients suffering from pathological conditions associated with diabetes mellitus.
Diabetes mellitus (DM) is a complex chronic disorder of carbohydrate, fat, and protein metabolism that results primarily either from a partial or complete lack of insulin secretion by the beta cells of the pancreas or from defects in cellular insulin receptors. DM is the sixth leading cause of death from disease in the United States. According to the American Diabetes Association, approximately 12-14 million Americans have diabetes. It is estimated, however, that more than half of these people have yet to be formally diagnosed to have this disease.
Two types of diabetes are recognized. Type I diabetics are patients dependent upon exogenous insulin to prevent ketoacidosis. Accordingly, these patients are said to suffer from Insulin-Dependent Diabetes Mellitus (IDDM), previously known as juvenile-onset, brittle, or ketosis-prone diabetes. Type II diabetics are those with Non-Insulin-Dependent Diabetes Mellitus (NIDDM), and were previously designated as having maturity-onset, adult-onset, ketosis-resistant, or stable diabetes.
The pathological complications of diabetes are fundamentally related to hyperglycemia (Porte Jr et al. 1996). While presently not well understood, the mechanisms involved in these complications are beginning to be elucidated. For example, it appears that hyperglycemia can induce increased aldose reductase activity which affects sorbitol accumulation, depletes neural myoinositol, and alters Na-K ATPase activity. Hyperglycemia also increases diacylglycerol and .beta..sub.2 protein kinase C activity, which in turn alters the contractility and hormone responsiveness of vascular smooth muscle, and alters endothelial cell permeability (Ishii et al. 1996). Moreover, hyperglycemia is associated with accelerated non-enzymatic glycosylation processes which activate endothelial and macrophage receptors for advanced glycosylation endproducts (AGEs), and alters lipoproteins as well as matrix and basement membrane proteins. Clearly, the consequences of glucose toxicity are globally distributed throughout the physiology of the diabetes patient.
Characteristically, the course of the disease is progressive, and includes polyuria, polyphagia, polydipsia, weight loss, hyperglycemia, and glycosuria. Numerous organ systems can be affected pathologically, including the eyes (resulting in retinopathy and cataract of the lens), kidneys (resulting in nephropathy), nervous system (resulting in neuropathy), circulatory system (resulting in angiopathy), teeth (resulting in periodontitis), bone (resulting in osteopenia), and skin. Diabetic retinopathy is one of the leading causes of blindness in the United States. Nephropathy leads to kidney failure, which can require dialysis, and is life-threatening. The goal of treatment is to reduce hypoglycemia, and to moderate or eliminate the effects of these pathologies. Typically, success is critically dependent on maintaining insulin-glucose homeostasis.
Currently, diabetes mellitus is managed by means of a controlled carbohydrate diet and daily insulin injections, or by hypoglycemic agents such as the short-acting agents acetohexamide, tolbutamide, tolazamide, and long-acting agents chlorpropamide, glipizide, and glyburide.
The Diabetes Control and Complications Trial (DCCT), a ten-year study completed in mid-1993, demonstrated that tight or "intensive" control of blood glucose levels-i.e., frequent self-monitoring of glucose levels and maintenance of these levels as close as possible to those in nondiabetics-significantly reduces diabetes-associated complications, such as retinopathy, nephropathy and neuropathy (DCCT Research Group 1993). As defined in the DCCT, "intensive" control meant that the diabetic patient followed a strict regimen, including controlling glucose tightly by three or more daily insulin injections or by means of an insulin pump. Intensive control was distinguished from a more moderate regimen termed "conventional" control, which included only one or two injections of insulin a day and less frequent monitoring of blood glucose concentration. The DCCT showed that the frequency of health complications was 40-75% lower for persons in the intensive control group than for those in the conventional treatment group (DCCT Research Group 1993). It has since become a central doctrine of diabetic management that the intensive control of hyperglycemia is critical to effective retardation or delay in the appearance or progression of the late complications of the disease.
Diabetic patients are taught to recognize the signs of impending hypoglycemia and insulin shock (e.g., headache, hunger, nervousness, irritability, diaphoresis, thready pulse, tremors and slurred speech). Hypoglycemia can be seen in both subsets of diabetics (IDDM and NIDDM) and is caused by either too much insulin or inadequate caloric intake (CDC Guide). However, it was also found in the DCCT that patients in the intensive treatment group more often suffered from seizures or coma or required another person's assistance to recover from hypoglycemia than did patients treated less intensively. The chief adverse complication associated with intensive therapy was 3-fold increase in the incidence of severe hypoglycemia, defined as the need for assistance from others, as compared to diabetics undertaking conventional therapy (DCCT Research Group 1993).
This observation is attributed to the unusual and interesting feature of the brain that, while like other organs systems in its reliance on blood glucose concentration for function, the brain differs from other organs in that it does not need insulin to utilize glucose. Boyle et al. (1995) have reported that hypoglycemia is likely to lead to a reversible, maladaptive central nervous system tolerance to subnormal plasma glucose concentrations. Specifically, certain autonomic portions of the brain adapt physiologically, learning to tolerate low blood glucose levels. By contrast, the rest of the brain, and in particular the cognitive portions, do not possess this capacity. Defective glucose counterregulation can occur even after only a single recent episode of hypoglycemia. Patients who experience repeated episodes of hypoglycemia often lose their capacity to recognize the symptoms typically associated with hypoglycemia or impending insulin shock, a condition called "hypoglycemia unawareness." Because the patient doesn't appreciate his or her own status, blood glucose levels can then fall so low that serious neurological problems ensue, including coma and seizure.
Thus, the danger in maintaining artificially a patient's blood glucose within the narrow, normal range-the essence of intensive control prescribed according to the DCCT--is that such regimens can induce recurrent low blood-glucose levels, raising the threat of seizure or a coma with little or no warning. Lewin (1996) has recognized that tight control of the blood glucose levels poses a difficult dilemma. Specifically, while tight control of blood glucose levels appears to be required to control hyperglycemia-associated pathology, in practice the patient often overcorrects, thereby inducing repeated episodes of hypoglycemia, giving rise to hypoglycemia unawareness.
Boyle et al. (1995) found that, because the body, and especially the brain, adapts to lower blood sugar levels, there is little margin between the blood glucose level at which hypoglycemic signs become perceptible and the level at which dangerous cognitive impairment occurs. Accordingly, patients with IDDM who use rigorous treatment regimens to maintain near-normal plasma glucose levels are at increased risk for seizures and comas. Boyle et al. conclude their article noting that their results would "challenge patients with IDDM and their physicians," due to the difficulty involved in achieving the tightest level of glycemic control (to minimize microvascular and other complications) while at the same time avoiding even a slight degree of hypoglycemia (to avoid central nervous system tolerance to subnormal glucose levels). However, Boyle et al. do not propose any specific therapeutic modality for meeting this challenge.
Porte Jr et al. (1996) have also commented on this tight-control dilemma. They point out that "g!lucose is a molecule essential for life," but they emphasize "its concentration must be carefully controlled because of the powerful adverse effects of both too much and too little glucose." Porte Jr et al. conclude "the obstacles to the complete understanding of glucose toxicity and its prevention are formidable." There is a clear need for additional understanding of these interrelated physiological processes, as well as for new diabetes treatment regimens that avoid the problems that have so far plagued effective patient management.
Tetracyclines are a class of compounds that are particularly well known for their early and spectacular success as antibiotics. Such compounds as tetracycline, sporocycline, etc., are broad spectrum antibiotics, having utility against a wide variety of bacteria and other microbes. The parent compound, tetracycline, has the following general structure: ##STR1## The numbering system for the multiple ring nucleus is as follows: ##STR2##
Tetracycline, as well as the 5-OH (terramycin) and 7-Cl (aureomycin) derivatives, exist in nature, and are all well known antibiotics. Semisynthetic derivatives such as the 7-dimethylamino derivative (minocycline), are also known antibiotics. The use of tetracycline antibiotics, while generally effective for treating infection, can lead to undesirable side effects. For example, the long-term administration of antibiotic tetracyclines can reduce or eliminate healthy flora, such as intestinal flora, and can lead to the production of antibiotic resistant organisms or the overgrowth of opportunistic yeast and fungi. These side-effects of long-term tetracycline therapy can be particularly disadvantageous to patients with diabetes because these patients tend to be abnormally highly susceptible to infection and impaired wound healing, which might at some juncture require antibiotic therapy to combat infection. Diabetes patients, in particular, tend to develop chronic yeast infections even without complications associated with antibiotic use.
Natural tetracyclines may be modified without losing their antibiotic properties, although certain elements of the structure must be retained to do so. Recently, however, a class of compounds has been defined that are structurally related to the antibiotic tetracyclines, but which have had their antibiotic activity substantially or completely extinguished by chemical modification. The modifications that may and may not be made to the basic tetracycline structure have been reviewed by Mitscher (1978). According to Mitscher, the modification at positions 5-9 of the tetracycline ring system can be made without causing the complete loss of antibiotic properties. However, changes to the basic structure of the ring system, or replacement of substituents at positions 1-4 or 10-12, generally lead to synthetic tetracyclines with substantially less, or essentially no, antimicrobial activity. For example, 4-de(dimethylamino)-tetracycline is commonly considered to be a non-antibacterial tetracycline. These compounds, known as chemically-modified tetracyclines (CMTs) have been found to possess a number of interesting properties, such as the inhibition of excessive collagenolytic activity both in vitro and in vivo. See, for example, Golub et al. (1991).
Tetracycline compounds have been observed to prevent or inhibit a variety of conditions, many of which are also recognized as diabetic complications. For example, tetracyclines inhibit non-enzymatic glycosylation of proteins. See, e.g., U.S. Pat. No. 5,532,227 to Golub et al., the entire disclosure of which is incorporated herein by reference. Tetracyclines, administered at both antimicrobial levels and at non-antimicrobial levels, have been known to play a role in reducing the activity of collagenase and other collagenolytic matrix metalloproteinases. Glycosylation and collagenolytic activity both may be related to a number of diabetic complications such as retinopathy, neuropathy, nephropathy, angiopathy, periodontitis, and impaired wound healing. Diabetics have connective tissue changes that can contribute to diabetic complications, such as reduced collagen solubility and decreased collagen synthesis. In diabetics, tetracyclines can prevent excessive collagen cross-linking (premature aging) and its associated complications, in addition to increasing collagen synthesis leading to an increase in newly synthesized, soluble uncross-linked collagen.
Tetracyclines have also been shown to reduce other pathophysiological complications characteristic of diabetes. For example, these compounds reduce or prevent proteinuria and albuminuria, related to nephropathy. It is also known that tetracyclines are capable of preventing cachexia or wasting in diabetic animals. Tetracyclines can inhibit abnormal lipid metabolism which has been associated with diabetic angiopathy and neuropathy. Moreover, it has been demonstrated that tetracyclines can inhibit nitric oxide synthetase (NOS), a potent natural vasodilator that is elevated in the presence of the effector cytokine, IL-1. Nitric oxide may also contribute to both diabetic nephropathy and angiopathy.
Applicants, however, are not aware of any evidence in the prior art disclosing or suggesting that tetracycline compounds could be of any use in modifying the most fundamental treatment modality for diabetes: the regulation of hyperglycemia by administration of insulin.
In view of the above considerations, it is clear that existing methods for controlling diabetes mellitus are limited in a number of ways. For example, the existing art does not provide efficient means for treating patients suffering from diabetes mellitus to avoid complications from either too much or too little blood glucose. Currently available treatment modalities are either too intrusive, e.g., insulin pumps, or require too much monitoring and intervention by the patient, e.g., tight control regimens, and yet they still fail to find safe passage between the Scylla of hypoglycemic neuropathology and the Charybdis of hyperglycemic tissue glycosylation and organ pathology.
Accordingly, it is one of the purposes of this invention to overcome the above limitations in the practice of medicine, by providing a method of treating patients suffering from diabetes mellitus that avoids the perils inherent in conventional treatment regimens.